Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome

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Abstract

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14 years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared with controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation.

Introduction

One of the earliest developmental processes in brain is the formation of the ventricular system and the associated septum separating the two chambers (Galarza et al., 2004). Typically, from months 2 to 5 of embryonic and fetal development, the lateral ventricles elongate and expand laterally away from the midline along with the expansion of the cerebral cortex. The anterior, posterior, and inferior horns as well as the bodies of the lateral ventricles become delineated and larger through month 7 of development. The septum pellucidum forms a medial wall between the body and the anterior horn of the lateral ventricles. Incomplete fusion of the laminae can manifest as one or two separate cavities: a cavum septum pellucidum (CSP) and a cavum vergae (CV).

Anatomically, the CSP is defined anteriorly by the genu of the corpus callosum, superiorly by the body of the corpus callosum, posteriorly by the anterior limb and pillars of the fornix, and inferiorly by the rostrum of the corpus callosum and the anterior commissure. In prenatal month 5, anterior to posterior and superior to inferior consolidation of the corpus callosum begins. The rostrum of the corpus callosum links the genu and the lamina terminalis while the fornix remains relatively stationary and the forceps minor grow to the frontal lobes by month 7. As callosal consolidation occurs, the leaflets of the septum pellucidum are drawn together and towards the lamina terminalis, closing the CSP from rostrum to fornix. Typically, the more anterior CSP is separated from the posterior CV by the anterior columns of the fornix. If the fornix is insufficiently fused with the corpus callosum, the CSP and CV will form into one continuous cavity (Born et al., 2004). In 15% of typically developing (TD) infants, the laminae fuse within 1 month post-partum, with the majority (85%) showing laminae fusion within 6 months.

The mechanisms by which the septum pellucidum closes and by which a CSP is maintained are still not completely understood (Shashi et al., 2004), but fusion of the laminae depends on the normal development of surrounding structures, particularly the hippocampus and the corpus callosum (Sarwar, 1989). Galarza et al. (2004) suggest several possible modulators of CSP maintenance, including primary atrophy in the form of reduced frontal and temporal lobe volumes and overall hemispheric volume reduction with ventricular enlargement. Support for this mechanism includes the common clinical neuroimaging correlation of CSP with brain anomalies characterized by global decrease in cerebral mass, such as in the pachygyria–lissencephaly spectrum and non-specific microcephaly (personal observation, JP). The proposal that laterally applied pressure, such as would be expected from increasing lobar volumes in normal brain development, can close the CSP is suggested by the observation of transient closure in a premature baby with hydrocephalus resulting from an intraventricular bleed (Needelman et al., 2006). Reduced connectivity (with resultant decreased tractional force exerted in an anterolateral direction) between the genu of the corpus callosum (the anterior border of the septum pellucidum) and the frontal lobes might also result in the maintenance of a CSP anteriorly. Since the corpus callosum also provides the superior attachment of the septum pellucidum, aberrant development leading to more lateral displacement could also result in less transmission of mass from superolateral cortical structures through the midline structures, which could in turn lead to maintenance of a CSP as well. CSP has also been noted with increased frequency in developmentally delayed individuals, suggesting it is commonly related to cerebral dysgenesis of many types (Bodensteiner and Schaefer, 1997). Indeed, it has been suggested that a wide CSP may be a non-specific marker for disturbed development (Bodensteiner and Schaefer, 1990).

We have informally observed enlarged CSP in a large number of children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in the course of collecting and reviewing structural brain imaging data over the last several years. van Amelsvoort et al. (2001) report a CSP/CV incidence rate of 40% in adults with 22q11.2DS versus a matched control group. Consistent with this, Campbell et al. (2006) reported a 69% incidence rate of midline anomalies, in particular those of CSP/CV, in children with 22q11.2DS versus 35% of sibling controls. Shashi et al. (2004) reported the presence of CSP in 4 of 13 children with 22q11.2DS making it the most common midline brain anomaly in their sample of non-psychotic children with the chromosomal deletion. 22q11.2DS encompasses the phenotypes of DiGeorge (1965), velocardiofacial (Shprintzen et al., 1978), and several other syndromes and is caused by hemizygous 1.5–3.0 Mb interstitial deletions on the q11 band of chromosome 22 (Driscoll et al., 1992). 22q11.2DS prevalence is between 1:2000 and 1:5000 live births (Oskarsdottir et al., 2004, Shprintzen, 2008) and is characterized by T-cell abnormalities, cleft palate, heart defects, facial dysmorphisms, and neonatal hypocalcemia (McDonald-McGinn et al., 1999, Antshel et al., 2005). Impairments or delays in language production and comprehension, visuospatial and numerical processing (Moss et al., 1999, Swillen et al., 1999, Bearden et al., 2001, Woodin et al., 2001, Simon et al., 2005a) and executive function (Sobin et al., 2004, Bish et al., 2005) are common, with mean IQ typically ranging from 70 to 85 (Woodin et al., 2001).

Given our recently stated position that midline anomalies of the brain may be at the root of many of the cognitive impairments experienced by those with 22q11.2DS (Simon, 2008), it may be that further understanding of this phenomenon could highlight an important early detectable biomarker for later neurocognitive dysfunction or even help to explain the mechanism by which the later impairments are created. However, to the best of our knowledge, specific quantification of CSP volumetric variability in children with 22q11.2DS has not been undertaken. Furthermore, most analytical studies of CSP have reported measurements of length and width (Born et al., 2004, Filipović et al., 2004), but few groups have examined CSP in volumetric terms (Crippa et al., 2006, Brisch et al., 2007). Since CSP is an anomaly that consists of a complex three-dimensional volume, strictly linear parameters such as length and width are unable to fully characterize its extent. Thus, volumetric measurements provide more accurate information than linear measurements about the true size of the cavum (Crippa et al., 2006).

The purpose of the current study was to both replicate and extend the existing literature on brain dysmorphia with a specific focus on CSP in children with 22q11.2DS. To this end, we used high-resolution magnetic resonance imaging (MRI) to specifically quantify and compare CSP volumes in children with chromosome 22q11.2DS and TD controls of a similar age. We hypothesized that CSP would be present more often in children with 22q11.2DS versus TD children. We also hypothesized that CSP lengths and volumes would be larger in children with 22q11.2DS versus typical controls.

Section snippets

Participants

Participants were 45 children with 22q11.2DS as confirmed by fluorescence in-situ hybridization (20 male, 25 female; mean age = 10 years, 5 months, S.D. = 1 year, 11 months) and 35 TD children (22 males, 13 females; mean age = 10 years, 10 months, S.D. = 2 years, 2 months) recruited at the Children's Hospital of Philadelphia (CHOP), the Hospital of the University of Pennsylvania (HUP), and at the University of California, Davis (UCD). After description of the study, assent was obtained from the child

Prevalence by group and gender

The proportion of children with CSP of any size was greater in children with 22q11.2DS (38 out of 45; 84.4%; χ2 (1) = 7.36, P = 0.007) versus TD controls (20 out of 35; 57.1%). The overall proportion of having any CSP did not statistically differ (χ2 (1) = 0.076, P = 0.78) between males (31 out of 42; 73.8%) and females (27 out of 38; 71.1%). Within each group, the proportion of males to females with any CSP did not differ from expectation in the 22q11.2DS (χ2 (1) = 0.85, P = 0.44) or TD (χ2 (1) = 0.57, P = 

Discussion

Here, we report a detailed analysis of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome in comparison to typically developing controls including, for the first time, volumetric CSP measurements. Consistent with the only previous report on CSP incidence in children with 22q11.2DS (Campbell et al., 2006), we found that atypical CSP length occurs with significantly greater frequency in children with 22q11.2DS than in TD controls. Based on the CSP classification scheme

Acknowledgements

The authors thank the children who took part in this study and their families. They also thank the 22q and You Center at Children's Hospital of Philadelphia for their support of the early phases of this study. Funding for this project was through grant NIHR01HD42974 awarded to Tony J. Simon. There are no conflicts of interest, financial or otherwise, for any of the authors.

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